MXPA00011060A - Novel 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones with anti-asthmatic, anti-allergic, anti-inflammatory, immuno-modulating and neuro-protective effect, method for the production and use thereof as a medicament - Google Patents

Abstract

The invention relates to novel 1,2,5-tri-substituted 1,2-dihydro-indazol-3-ones and to a method for the production and the pharmaceutical use thereof. The compounds have anti-asthmatic, anti-allergic and anti-inflammatory immuno-modulating and neuro-protective effects.

Description

NEW 1, 2-DIHYDRO-INDAZOL-3-ONAS 1, 2, 5-TRISUBSTITUIDAS WITH ACTIVITY ANTIASMATICA, ANTIALERGICA, INHIBIDORA DE INFLAMMATIONS, IMMUNOMODULANT AND NEUROPROTECTING, PROCESSES FOR ITS PREPARATION AND ITS USE AS MEDICINES DESCRIPTION OF THE INVENTION Technical Field The invention relates to the preparation and use of new indazol-3-one derivatives as a medicine with antiasthmatic, antiallergic, inhibitory properties of inflammations, immunomodulants and neuroprotective properties. STATE OF THE ART Cyclosporin A (CsA) and FK 506 are natural immunosuppressive substances that come from fungi, which inhibit in some cell types the Ca2 + -dependent signal transmission pathway. In T cells both compounds inhibit the transcription of a series of genes. CsA and FK506 both bind with high affinity to soluble receptor proteins such as, for example, cyclophilin (Cyp) or the binding protein of FK-506 (FKBP) (G. Fischer et al., Nature 337 (1989), 476-478; M. W.

Harding et al., Nature 341 (1989), 755-760). The complex formed by CsA-Cyp and by FK506-FKBP binds calcineurin (CN) and inhibits its phosphatase activity.

The cytosolic, phosphorylating component of the transcription factor NF-AT was recognized as cellular target molecule of CN, so that in the absence of CN activity the active transcription complex can not be connected to the IL2 promoter (MK Rosen, SL Schreiber , Angew, Chem., 104 (1992), 413-430, G. Fischer, Angew, Chem. 106 (1994), 1479-1501). Allergic and asthmatic diseases are caused by a inflammation reaction controlled by T cells and their mediators. To date, corticosteroids are still the remedy chosen for the treatment of many allergic diseases. It was found in both animal experiments and clinical studies that CsA and FK 506 are also a suitable therapeutic agent in the case of bronchial asthma and the inflammations that motivate it. Despite the multitude of preparations to identify new active inhibitors of the immunophilin, to date it has not been possible to elaborate or isolate more effective structures than CsA, FK 506, rapamycin or derivatives of these natural substances. However, the high inhibitory potential of CsA, FK 506 and rapamycin is greatly reduced due to the wide variety of side effects, in particular nephrotoxicity (NH Sigal et al., J. Exp. Med 173 (1991), 619 -6128). The background of this fact is the lack of specificity of the interaction between the immunofilin binders and the specific binding proteins of the cells. Due to this, the known medicinal therapeutic effect of these immunosuppressants is considerably limited. In addition, the lack of selectivity of the compounds is problematic, precisely in the prolonged therapies. Substances that inhibit the activity of peptidylprolylisomerases (PPlases) such as Cyp or FKBP possess neuroprotective properties, stimulate neuronal growth and are suitable for the treatment of neurodegenerative diseases (WO 96/40140, US 5,696,135, WO 97/18828). Substituted indazole derivatives are known which, however, differ from the claimed compounds with respect to the substituents X, Y, Z, R1, R2 and R3 and their pharmacodynamic effect. Baiocchi et al. (Synthesis 1978 (9), 633-648) provide a synopsis with respect to the synthesis and properties of l, 2-dihydro-3H-indazol-3-ones. Schindler et al (WO 97/34874) describe 1, 3, 5-trisubstituted indazoles with anti-asthmatic, anti-allergic, inflammatory-inhibiting and immunomodulatory activity.

EP 0 199 543 contains 1,6-disubstituted 1,2-dihydro-indazol-3-ones and their use for pharmaceutical purposes. WO 94/24109 contains indazole derivatives suitable for the treatment of HIV infections. Ketami et al. (J. of Heterocycl, Chem. 7 (4), 807-813 (1970)) describes 1, 1,5-disubstituted 2-dihydro-indazol-3-ones. US 3,470,194 mentions the formation of (1, 2-dihydro-3-oxy-indazol-2-yl) alkanic acids in the case of using polar solvents. K. v. Auwers (Ber. Dtsch. Chem. Ges. 58. 2081-2088 (1925)) and K. v. Auwers et al. (Justus Liebigs Ann, Chem. 451. 281-307 (1927)) describe the constitution of acyl-indazoles and their migration. Zoni et al. (II Drug Ed. Sci. 23 (5). 490-501 (1968)) and Zoni et al. (Boil, Chim. Farm, 107, 598-605 (1968)) describe the alkylation of 1-substituted lH-indazole-3-ol. Evans et al. (Tetrahedron 21,3351-3361 (1965)) describe the synthesis of 1,3-substituted acyl and tosyl-indazoles.

Tse et al, (Arch. Pharm. 329 (1) .35-40 (1996)) report on the anti-inflammatory properties of N-substituted indazoles. Anderson et al. (J. Chem Soc. C. 3313-3314 (1971)) describe 1, 3-substituted tosyl-indazoles. Palazzo et al. (J. Med. Chem 9. 38-41 (1966)) and Gyula et al. (Acta pharm. Hung, 44, 49-57 (1974)) describe the synthesis of 2-dimethylaminoalkyl-1-phenyl-indazol-3-ones. Klicnar (Coll. Czech, Chem. Comm. 42. 327-337 (1977)) describes acetyl-indazoles. Tserng et al. (J. Org. Chem. 38.3498-3502 (1973)) describes the synthesis of 1,2-disubstituted 1,2-dihydro-indazol-3-ones. Aran et al. (Heterocycles 45, 129-136 (1997)) describes the selective synthesis of 2-substituted indazol-3-ones without substitution N-1. Aran et al. (Liebigs Ann., 1996, 683-691), Aran et al. (Liebigs Ann, 1995, 817-824) and Aran et al. (J. Chem. Soc. Perkin Trans I, 1119-1127 (1993)) describe 1,2-substituted 5-nitro-indazol-3-ones and their cytostatic activity. Bruneau et al. (J. Med. Chem. 34. 1028 1036 (1991)) describe 1 and 2-substituted indazol-3-ones as inhibitors of 5-lipoxygenase.

Wyrick et al. (J. Med. Chem. 27. 768-772 (1984)) describe 1,2-disubstituted indazol-3-ones with cholesterol-lowering activity. Schmutz et al. (Helv. Chim. Acta 47. 1986 1986 (1964)) describe the alkylation of indazolones. Yamaguchi et al. (Chem. Pharm Bull (43 (2). 332-334 (1995)) describe 2-substituted (l-pyridin-3-yl) -indazol-3-ones and their antiasthmatic activity. secondary to the preparations introduced, the deficiency in the curative successes and the therapy so far not very specific, in the case of the treatment of asthmatic diseases there remains a great need for compounds with high effectiveness and safety. of finding and providing, by specific synthesis, new rotamase inhibitor compounds and / or characteristics of inhibition of pulmonary infiltration of eosinophils A totally novel class of substances that surprisingly binds specifically immunophilins constitutes the compounds of formula I according to The invention This class of compounds has a high affinity to immunophilins such as CypB.

Embodiment of the invention Surprisingly it was now discovered that the novel indazole derivatives are able to inhibit the activity of PPlase. Therefore, these compounds are of great significance for the manufacture of drugs in which the inhibition of PPlase is useful. Such diseases are, for example: peripheral neuropathies, neurodegenerations, apoplectic attacks, Parkinson's and Alzheimer's diseases, traumatic brain diseases, multiple sclerosis. It was also found that the compounds according to the invention are able to inhibit tissue migration, characteristic of eosinophilic granulocytes in the late phase asthmatic reaction. The invention relates to 1,2, 5-trisubstituted 1,2-dihydro-indazol-3-ones of the general formula I formula I Where X, Y, Z, R1, R2 and R3 have the following meaning: X can be -S02-, -SO-, - (CH2) P-, - (CH2) p-0-, - (CH2) P- (C = 0) -, - (CH2) p- (C = 0) ) -NH-, - (CH2) p-CHOH-, -CHOH- (CH2) p-, - (CH2) P-CH = CH-, -CH = CH- (CH2) P- with p = 1 ... 4, Y can be - (C = 0) -, - (C = 0) -NH- , - (0 = 0) -NH- (CH2) P-, - (C = 0) - (CH2) p-, - (CH2) P-, - (CH2) p-0-, - (CH2) p - (C = 0) -, - (CH2) P- (C = 0) -NH-, - (CH2) p- (C = 0) -NH- (CH2) p-, - (CH2) p-CHOH -, -CHOH- (CH2) p-, - (CH2) P-CH = CH-, -CH = CH- (CH2) p- with p = 1. ..4, Z can be -0-, -0- (CH2) p- with p = 1 ... 4, -NH-, -NH- (C = 0) -, -NH- (C = 0) -NH-, -NH- (C = 0) -0-, -NH-CH2- (C = 0) - and -NH- (C = 0) -CH2-, R1, R2 and R3 can be the same or different and having the following meaning: mono, bi or tricyclic saturated or mono- or polyunsaturated carbocycles with 5 ... 14 ring members, in particular phenyl, naphthyl, anthranil, fluorenyl; or mono, bi or tricyclic saturated or mono- or polyunsaturated heterocycles with 5-15 ring members and 1 ... 6 heteroatoms, which preferably are N, 0 and S, in particular thiophenyl, pyridinyl, isoxazolyl, benzimidazolyl, benzyl (1) , 3) dioxolyl, pyrimidinyl, quinolyl, quinazolinyl, morphononylyl, pyrrolidinyl, pyrrolyl, phenyl (1, 2, 4) oxadiazolyl, phenylthiazolyl, wherein carbocycles or heterocycles may be mono- or polysubstituted with: C? ... 6 ~ alkyl, -0-C? ... 6-alkyl, -0-C3-cycloalkyl, mono, bi or tricyclic carbocycles saturated or mono- or polyunsaturated with 3 ... 14 ring members, heterocycles mono, bi or tricyclics saturated or mono or polyunsaturated with 5-15 ring members and 1 ... 6 heteroatoms, which preferably are N, 0 and S, -F, -Cl, -Br, -I, -OH, -SH, -N02, -NH2, -NHC? ... 6- alkyl, -N (C? ... 6-alkyl) 2, -NHC6 ...? 4-aryl, -N (C6 ... ? -aryl) 2-N (C? ... 6-alkyl) (C6 ...? -aryl), -NHC0C? ... 6- alkyl, -NHCOC6 ...? -aryl, -C0NHC ?. ..6-alkyl, CONHC6 ...? 4-aryl ?, -CONHS02C? ... 6-alkyl, -CONHS02C6 ... 14-aryl, -CN, - (CO) C? ... 6-alkyl , - (CS) C? ... 6-alkylof-COOH, -COOC? ... 6-alkyl, -0-C6 ...? 4-aryl, -O- (CO) C? ... 6 - alkyl, -O- (CO) C6 ...? 4-aryl, benzyl, benzyloxy, -S-C? ... 6-alkyl, -S-C6 ...? -aryl, -CF3, - ( CH2) p-C00H with p = 1 to 4, - (CH2) p-COOC? ... 6-alkyl with p = 1 to 4, -S02-C? ... 6-alkyl, -S02- C6. ..? - aryl, R1 can also be H (however not when X = CH2) R -Z can also be N02. The compounds according to the invention are new, but with the exception of the compounds according to the formula I: When Z is equal to -NH- (C = 0) -, -NH- (C = 0) -NH -, -NH- (C = 0) -CH2- and simultaneously R1 = phenyl mono or poly substituted with -COOH, -COOC? ... 6-alkyl, - (CH2) p-COOH with p = 1 to 4, - (CH2) p-C00C? ... 6-alkyl with p4, -C0NHC? ... 6-alkyl, -CONHC6 ...? -aryl, -CONHS02C? ... 6-alkyl, CONHS02C6 .. 4-aryl, lH-tetrazol-5-yl, then R2 can not be equal to phenyl mono- or polysubstituted with CN, halogen, C? ... 4-alkyl, C? ... -alkyloxy, CF3. When R3-Z = N02, then Rx-X and R2-Y can not simultaneously have the following meaning: Rx-X = benzyl, 4-methoxybenzyl Rz-Y = benzyl, 2-picolyl. The invention also relates to physiologically tolerable salts of the compounds according to formula I. The physiologically acceptable salts are obtained in the usual manner by neutralizing the bases with inorganic or organic acids, or else by neutralizing the acids with inorganic or organic bases. Suitable as inorganic acids, for example, hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, such as organic acids, for example, carboxylic acids, sulfo acids or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, acid glycolic, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3 -aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene -2-sulfonic. Suitable as inorganic bases, for example, sodium hydroxide, caustic potash, ammonia, as well as organic bases, the amines, but preferably preferably tertiary amines such as trimethylamine, triethylamine, pyridine, N, N-dimethylaniline, quinoline, isoquinolone. , α-picoline, β-picoline, β-picoline, quinaldine or pyrimidine. In addition, the physiologically acceptable salts of the compounds according to formula I can be obtained by converting derivatives containing tertiary amino groups into the quaternary ammonium salts, in a manner known per se with quaternizing agents. Suitable quaternizers are, for example, alkyl halides such as methyloduro, ethyl bromide, and n-propylchloride, but also arylalkyl halides such as benzyl chloride or 2-phenylethylbromide. The invention also relates to the compounds of the formula I containing an asymmetric carbon atom, with the mixtures with D-form, L-form and D, L mixtures, as well as with the diastereomeric forms in the case of several asymmetric carbon atoms. . Those compounds of formula 1 which contain asymmetric carbon atoms and which are generally obtained as racemates can be separated into the optically active isomers in a manner known per se., for example with an optically active acid. However, it is also possible to use an optically active starting substance from the beginning, since a corresponding optically active compound or diastereomer is obtained as a final product. The object of the invention is the preparation and use of the compounds according to the invention or of their physiologically tolerable salts such as: 1 rotamase inhibitors for the preparation of medicaments for the treatment of diseases transmitted by this enzyme and / or 2 inhibitors of late phase eosinophilia for the preparation of drugs for the treatment of diseases transmitted by these cells. These diseases include, for example, peripheral neuropathies, neurodegeneration, stroke, Parkinson's and Alzheimer's diseases, traumatic brain diseases, multiple sclerosis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammations. mediated by eosinophils such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome. Autoimmune diseases, such as rheumatoid arthritis, rheumatoid spondylitis, lupus erythematosus, psoriasis, glomerulonephritis and uveitis. Insulin-dependent diabetes mellitus and sepsis. The compounds according to the invention or their physiologically tolerable salts are also used for the preparation of medicaments which prevent rejection reactions after cell, tissue or organ transplants. For the production of the medicaments, in addition to the usual adjuvants, vehicles and fillers, an active dose of the compounds according to the invention or their salts is used. The dosage of the active ingredients can be varied according to the route of administration, the age, the weight of the patient, the type and severity of the diseases to be treated, and similar factors. The daily dose can be administered as a single dose to be administered once, or subdivided into 2 or more daily doses, and is usually 0.001-1000 mg. As forms of application, oral, parenteral, intravenous, transdepthic, topical, inhalative and intranasal preparations are considered. The usual galenic preparation forms are administered, such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrup, juices or drops. The solid forms of medicament may have adjuvants and inert carriers, such as, for example, calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methylcellulose, talc, acids. highly dispersed silicas, silicone oil, high molecular weight fatty acids (such as stearic acid), gelatins, agar-agar or fats and oils of vegetable and animal origin, high molecular weight solid polymers (such as polyethylene glycol); preparations suitable for oral administration may contain, if desired, additional flavors and / or sweeteners. The liquid medicament forms can be sterilized and / or optionally contain adjuvants such as preservatives, stabilizers, crosslinkers, penetration aids, emulsifiers, debonding agents, dissolution promoters, salts, sugar or sugar alcohols to regulate the osmotic pressure and / or for regulation and / or viscosity regulators. Such additives are, for example, tartrate and citrate regulator, ethanol, complexing agents (such as tetraacetic acid of ethylenediamine and its non-toxic salts). To regulate the viscosity, high molecular weight polymers are suitable, such as, for example, liquid polyethylene oxide, microcrystalline celluloses, carboxymethyl celluloses, polyvinyl pyrrolidones, dextrans or gelatin. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatins, agar-agar, calcium phosphate, magnesium stearate, fats. of animal and vegetable origin, solid polymers of high molecular weight, such as polyethylene glycol. Oily suspensions for parenteral or topical applications can be synthetic or vegetable-type synthetic oils, for example liquid esters of fatty acids with respectively 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid , tridecanic acid, margaric acid, stearic acid, aracaric acid, myristic acid, behenic acid, pentadecanoic acid, linolic acid, elaidinic acid, brasidinic acid, erucic acid or oleic acid, esterified with primary to tertiary alcohols with 1 to 6 C atoms , such as, for example, methanol, ethanol, propanol, butanol, pentanol or its isomers, its glycol and glycerin isomers. This type of esters of fatty acids are, for example, commercial miglioles, isopropylmyristate, isopropylpalmitate, isopropyl stearate, 6-caprinic acid of PEG, ethyl esters of caprylic / capric acids of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, esters ethyl esters of waxy fatty acids such as synthetic fat from the tail glands of ducks, isopropyl ester of coconut fatty acid, oleic esters of oleic acids, decyl esters of oleic acids, ethyl ester of lactic acid, dibutyl phthalate, isopropyl ester of adipic acid, fatty acid esters of polyols and others. Also suitable are silicone oils of various viscosities or fatty alcohols such as isotridecylalcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids such as, for example, oleic acid. It is also possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil. Suitable solvents, binders and promoters of the solution are water or miscible solvents with water. Suitable, for example, are alcohols such as ethanol or isopropyl alcohol, benzylalcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerin, di- or tri-propylene glycol, waxes, methyl Cellosolv, Cellosolv, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc. Suitable film formers can be cellulose ethers which are dissolved or can be foamed, both in water and in organic solvents, such as, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches. Mixed forms between gel and film formers are also quite possible. In this case they find application, above all, ionic macromolecules, such as, for example, sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and their saltsSodium amylopectin semiglycolate, alginic acid or propylene glycol alginate such as sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. Additional adjuvants of the formulation can be used: glycerin, paraffin of various viscosities, triethylamine, collagen, allantoin, novantisolic acid. It may also be necessary for the formulation to use surfactants, emulsifiers or crosslinkers, such as sodium lauryl sulfate, fatty alcohol ether sulfates, Di-Na-N-lauryl-β-iminodipropionate, polyoxyethylated castor oil, or monooleate sorbitol, sorbitol monostearate, polysorbates (eg Tween), cetylalcohol, lecithin, glycerin monostearate, polyoxyethylene-stearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride or monoethanolamine-orthophosphoric acid mono / dialkyl polyglycol ether salts. For the preparation of the desired formulations, stabilizers such as montmorillonite or colloidal silicic acids to stabilize emulsions, or antioxidants such as, for example, tocopherols or butylhydroxyanisole to prevent the decomposition of the active ingredients, or preservatives such as p-acid ester, may also be necessary if necessary. -hydroxybenzoic The production, filling and closing of the preparations is carried out under the usual antimicrobial and aseptic conditions. The dosage of the pharmaceutical preparations is a function of the age, condition and weight of the patient as well as the manner of application. In general, the daily dose of active principle is between 0.001-25 mg / kg of body weight. Preparation According to the present invention, the compounds of the general formula I can be prepared according to the following methods: Process for the preparation of the compounds of the general formula I, characterized in that a) for X = -S02-, -SO- is proceeded according to scheme 1. The esters of lH-indazol-3-ylsulfonic acid are reacted II in the presence of a base and optionally in the presence of a diluent to obtain compounds of the general formula III, wherein R1, R3, X and Z have the meaning mentioned above. The esters of IH-indazol-3-ylsulphonic acid II or 1-sulfonyl-indazoles III are reacted, optionally in the presence of a base, in particular sodium hydride, and optionally in the presence of a diluent, in particular dimethyl sulfoxide, with compounds of the following general formulas: Hal-Y-R2, 0 = C = N- (CH2) p-R2, (R2- (CH2) pC = 0) 20 with p = 0 ... 5 where R1, R2, R3, X, Y and Z have the abovementioned meaning and Hal means a halogen atom F, Cl, Br or iodine, to obtain compounds of the general formula I, where R1, R2, R3, X, Y and Z have the meaning previously mentioned.

Scheme 1: formula II formula III formula I b) for X = - (CH2) P-, - (CH2) p-0-, - (CH2) p- (C = 0) -, - (CH2) p- (C = 0) -NH-, - (CH2) p-CHOH-, -CHOH- (CH2) p-, - (CH2) p-CH = CH-, -CH = CH- (CH2) P- with p = 1 ... 4, comes from according to scheme 2. Compounds of the general formula III are reacted, optionally in the presence of a base, in particular pyridine or sodium hydride, and optionally in the presence of a diluent, in particular tetrahydrofuran or dimethyl sulfoxide, with compounds of the following general formulas : Hal-Y-R2, 0 = ON- (CH2) p-R2, (R2- (CH2) p-CO) 20 with p = 0. ..5 being that R1, R2, R3, X, Y and Z have the meaning mentioned above and Hal means a halogen atom F, Cl, Br or iodine, to obtain compounds of the general formula I, where R1, R2 , R3, X, Y and Z have the aforementioned meaning.

Scheme 2 formula III formula I being that formula III can also be found as a tautomeric form of formula IV according to scheme 3.

Scheme 3 Formula III Formula IV The compounds of the general formula I are new. EXAMPLES OF EMBODIMENTS Of the compounds according to the invention, the following representatives are mentioned by way of example: 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-methoxy-benzolsulfonyl) -1, 2 -dihydroindazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- (2-hydroxy) 5-Nitrobenzyl) -5-methoxy-1- (4-trifluoromethoxy-benzolsulfonyl) -1,2-dihydro-indazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-Chlorobenzole-sulfonyl) -1,2-dihydro-indazol-3-one 1- (4-fluorobenzolsul onyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1,2-dihydro- indazol-3-one N- (4- [2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-3-oxo-2,3-dihydro-indazol-l-sulfonyl] -phenyl) -acetamide 2- (4-fluorobenzyl) -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- (4-fluorobenzyl) -5-methoxy-1- (4-chlorobenzolesulfonyl) -1,2-dihydro-indazol-3-one 1- (4-fluorobenzenesulfonyl) -2- (4-fluorobenzyl) -5-methoxy-1,2-dihydro-indazol-3-one 2- (2-fluorobenzyl) -5 -methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 1- (4-fluorobenzenesulfonyl) -2- (2-fluorobenzyl) -5-methoxy-1,2-dihydroxy indazol-3-one 2- (3-methoxybenzyl) -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- (3-trifluoromethylbenzyl) -5-methoxy-l- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- [2- (4-chlorophenyl) thiazol-4-ylmethyl] -5-methoxy-l- (toluol-4-sulfonyl) - 1,2-dihydro-indazol-3-one 5-methoxy-2- (3-phenylalyl) -1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 5-methoxy-2- (3-oxo-3-phenylpropyl) -1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- [2- (2,6-difluorphenoxy) ethyl] -5-methoxy- l- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- [2- (2-bromo-4,6-difluorphenoxy) ethyl] -5-methoxy-1- (toluol-4 -sulfonyl) -1,2-dihydro-indazol-3-one 2- [2- (2-bromo-4,6-difluorphenoxy) ethyl] -5-methoxy-1- (4-methoxy-benzolsulfonyl) -1, 2-dihydro-indazol-3-one N- (4-. {2- 2- (2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-yl) ethyl] -5-methoxy -3-oxo-2, 3-dihydro-indazol-l-sulfonyl.} - phenyl) -acetamide 2-. { 3- [4- (3-chlorophenyl) -piperazin-1-yl] propyl} -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 1- (4-chlorobenzolsulfonyl) -2-. { 3- [4- (3-chlorophenyl) -piperazin-1-yl] propyl} -5-methoxy-l- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one N-benzyl-2- [5-methoxy-3-oxo-l- (toluol-4-sulfonyl) -1, 3-dihydro-indazol-2-yl] -acetamide 2- [5-methoxy-3-oxo-l- (toluol-4-sulfonyl) -1, 3-dihydro-indazol-2-yl] -N - (4-methoxyphenyl) -acetamide 2- (2,6-dichlorobenzoyl) -5-nitro-l- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 1- (3, 4- dichlorobenzyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methylthio-1,2-dihydro-indazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (3 -nitro-benzyl) -1, 2-dihydro-indazol-3-one (2-fluorophenyl) -amide of 5-methoxy-1- (3-nitrobenzyl) -3-oxo-l, 3-dihydro-indazole- 2-methoxy-l- (3-nitrobenzyl) -3-oxo-l, 3-dihydro-indazole-2-carboxylic acid 2-carboxylic acid (2-6-dichloro-phenyl) -amide (2-fluoro-6-trifluoromethylphenyl) 5-methoxy-1- (3-nitro-benzyl) -3-oxo-l, 3-dihydro-indazole-2-carboxylic acid amide 3- [2- (2-fluorophenylcarbamoyl) -5- methyl ester methoxy-3-oxo-2,3-dihydro-indazol-l-ylmethyl] -benzoic acid (2,6-dichloro-phenyl) -am l- (4-Fluoro-benzyl) -5-methoxy-3-oxo-l, 3-dihydro-indazole-2-carboxylic acid 1- (4-fluorobenzyl) -5-methoxy-4-nitrobenzyl ester 3-Oxo-l, 3-dihydro-indazole-2-carboxylic acid (2,6-dichloro-phenyl) -amide of 1- (2,6-difluorbenzyl) -5-methoxy-3-oxo-l, 3-dihydro- Indazole-2-carboxylic acid (2,6-dichloro-phenyl) -amide of 1- (2-chloro-6-fluorobenzyl) -5-methoxy-3-oxo-l, 3-dihydro-indazole-2-carboxylic acid The characterization of The compounds were made by melting point, thin layer chromatography, elemental analysis, NMR spectroscopy, IR and UV spectroscopy of AVI and finally mass spectroscopy. Purification by liquid column chromatography: When the compounds of examples 1 to 35 are prepared, the 1- and 3-O-substituted 1H-indazoles according to general formula V can be formed as by-products. formula V In general, the compounds of the general formula I can be separated by recrystallization from the compounds of the general formula V. If this does not succeed, a separation by column chromatography is required under the following conditions: Stationary phase: silica gel for normal phase, for example Si from 60 to 100 A. Particle size 5 to 100 μm. Eluent: methylene chloride / ethyl acetate = 95/5 or methylene chloride / methanol = 95/5. The compounds of the general formula I are more polar than the compounds of the general formula V, so that the compounds of the general formula I are eluted after the compounds of the general formula V under these chromatographic conditions. This purification process can be applied for all examples 1 to 35. Example 1 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-methoxy-benzole-sulfonyl) -1,2-dihydroindazole -3-one . 01 g (15 mmol) of 5-methoxy-lH-indazol-3-yl ester of 4-methoxy-benzenesulfonic acid are dissolved in 70 ml of DMSO and mixed in portions with 1.5 g (37.5 mmol) of sodium hydride ( to 60 percent). After stirring for 2 hours, a solution of 2.81 g (15 mmol) of 2-hydroxy-5-nitrobenzylchloride in 25 ml of DMSO is added dropwise and the mixture is stirred for 3 hours at 90-100 ° C. After cooling, 400 ml of water are added, the mixture is stirred for 3 hours and extracted three times with 400 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water, dried over sodium sulfate, distilled to dryness in vacuo and the residue recrystallized from ethanol. Yield: 3.0 g (41.1% of theory) F: 215-217 ° C 13 C-NMR (300 MHz DMSO): d = 46.0 CH2N; 55.8 2 x CH30; 165.1 C = 0 IR (KBr):? = 1669 cm "1 C = 0 According to an analogous way of proceeding, the compounds represented in table 1 are elaborated Table 1 formula VI R- i _ CH30 Example 25 2- (2,6-dichlorobenzole) -5-nitro-l- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one g (0.015 mol) of 5-nitro-lH-indazol-3-yl ester of toluol-4-sulfonic acid are dissolved in 50 ml of pyridine and stirred for 30 minutes at 80 ° C with 3.77 g (0.018 mol) of 2,6-dichlorobenzoylchloride. After cooling, it is suspended under stirring in 150 ml of water, mixed with 100 ml of 5 N HCl, separated by suction and washed with water. Purification of the crude product is carried out with preparative high performance liquid chromatography using silica gel 60 and the eluent methylene chloride / ethyl acetate 99/1. Yield: 2.4 g (32% of theory) F: 195-197 ° C (EtOAc) 13 C-NMR (300 MHz DMSO): d = 20.27 CH3; 159.33 C = 0; 162.87 C = 0. IR (KBr):? = 1726 cm "1 C = 0 Example 26 l-. {3,4-dichlorobenzyl) -2- (2-hydroxy-5-nitro-benzyl) -5-methyl-thio-1,2-dihydrohydrate indazol-3-one r O 'fv OH - 3.6 g (11 mmol) of 1- (3,4-dichlorobenzyl) -5-methylthio-lH-indazol-3-ol are dissolved in 100 ml of DMSO and mixed in portions with 0.34 g (13.2 mmol) of Sodium hydride (95 percent). After stirring for 2 hours, a solution of 2.1 g (11 mmol) of 2-hydroxy-5-nitrobenzylchloride in 20 ml of DMSO is added dropwise and the mixture is stirred at 60 ° C. for 3 hours. After cooling, 200 ml of water are added dropwise, stirred for 4 hours and separated by suction. The precipitate is stirred hot with methanol and recrystallized from 2-propanol. Yield: 1.0 g (18.5% of the theory) F: 225 ° C NMR-13C (DMSO-d6, 300 MHz): d = 13.7 CH3S; 48.8 2 x CH2N; 160.6 C = 0 IR (KBr):? = 1623 cm "1 C = 0 According to an analogous procedure, the compound represented in Table 2 is obtained using 5-methoxy-1- (3-nitrobenzyl) -lH-indazol-3-ol as the starting substance. : Formula VII R1 CH30 Example 28 5-Methoxy-1- (3-nitrobenzyl) -3-oxo-1,3-dihydro-indazole-2-carboxylic acid (2-fluorophenyl) -amide To a solution of 3.0 g (0.01 mol) of 5-methoxy-1- (3-nitrobenzyl) -lH-indazol-3-ol in 100 ml of tetrahydrofuran is added 1.8 g (0.013 mol) of 2-fluorophenylisocyanate, and Heat reflux for 4 hours. It is then concentrated to 20 ml, the precipitated sediment is separated by suction and recrystallized with ethyl acetate. Yield: 1.1 g (25% of theory) F: 149-151 ° C 13 C-NMR (300 MHz DMSO): d = 157.22 C = 0; 165.16 C = 0 IR (KBr):? = 1682, 1727 cm "1 C = 0 The compounds represented in table 3 are analogously processed.

Table 3 formula VIII R1 = CH30 To determine the characteristic anti-asthmatic, anti-allergic, inflammation-inhibiting and / or immunomodulating activity of the compounds according to the invention, in vitro and in vivo investigations were carried out. The compounds according to formula I according to the invention are surprisingly characterized by binding immunofilin, and inhibit their peptidyl-prolyl-cis-trans-isomerase (PPlase) activity. For the initial exploration (10 μmol / 1) inhibition of human cyclophilin B is determined in the PPlase assay. Assay for the determination of the activity and inhibition peptidilprolilisomerasa (PPlasa) Method The activity PPlasa is tested according to a known enzymatic test: G. Fischer, H. H. Bang, C Mech, Biomed, Biochim Acta 43 1101-1111, G. Fischer, H Bang, A. Schellenberger, Biochim. Biophys Acta 791 (1984), 87-97; D.H. Rich et al., J. Med Chem. 38 (1995), 4164-4170.

The compounds of the general formula I according to the invention are pre-incubated at 4 ° C for 15 minutes together with 10 nmol of Cyp B. The enzymatic reaction is initiated with the addition of chymotrypsin and HEPES regulator with the Suc-Ala assay peptide -Ala-Pro-Phe-Nan The modification of the extinction at 390 nm is then followed and evaluated. The modification of the extinction that is determined photometrically is due to two partial reactions: a) the rapid chymotryptic splitting of the trans peptide; b) non-enzymatic cis-trans isomerization catalyzed by cyclophilins. The inhibition of the PPlase activity determined for selected compounds of the general formula I is shown in table 4: Table 4 Inhibition of late phase eosinophilia 24 h after inhalation challenge with ovalbumin in actively sensitized guinea pigs Inhibition of eosinophilic pulmonary infiltration by substances is tested in an in vivo assay in Dunkin-Hartley male guinea pigs (200-250 g ) actively sensitized against ovalbumin (OVA). Sensitization is carried out by two intraperitoneal injections of a suspension of 20 μg of OVA in addition to 20 mg of aluminum hydroxide as an adjuvant in 0.5 ml of physiological saline solution per animal in two successive days. 14 days after the second injection, the animals are subjected to a previous treatment with mepyramine maleate (10 mg / kg i.p.) to protect them against anaphylactic death. 30 minutes later the animals are exposed for 30 seconds in a plastic box to an OVA spray (0.5 mg / ml), which is produced by an atomizer operated by compressed air (19.6 kPa) (allergenic provocation). The control animals were atomized with a physiological saline solution. 24 hours after the challenge the animals are anesthetized with an overdose of ethyl urethane (1.5 g / kg body weight i.p.) and a bronchoalveolar lavage (BAL) is carried out with 2 x 5 ml of physiological saline. The BAL liquid is collected, centrifuged at 300 rpm for 10 minutes and then the cell pellet is resuspended in 1 ml of physiological saline. Eosinophils are stained using a Becton-Dison assay kit (N. 5877) for eosinophils and counted in a Neubauer chamber. Each test is accompanied by 2 control groups (atomization with physiological saline and atomization with OVA solution). The percentage inhibition of the eosinophils of the test group treated with substance is calculated according to the following formula: (A - C) - (B - C) / (A - C) x 100 =% inhibition The test substances are applied intraperitoneally or orally as suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethylcellulose two hours before the allergenic challenge. The control groups are treated with the vehicle in a manner analogous to the manner of application of the test substance. The number of animals per control and test group is 3-10. The results are indicated in table 5. Table 5 A = eosinophils in the control group with provocation by OVA and vehicle B = eosinophils in the group elicited with OVA treated with substance C = eosinophils in the control group elicited with 0.9% NaCl and vehicle x = average value s = standard deviation Accordingly, the compounds according to the invention are particularly suitable for the preparation of medicaments for the treatment of diseases related to the inhibition of immunological processes.

Claims (10)

1. New 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones of the general formula I formula I Wherein X, Y, Z, R1, R2 and R3 have the following meaning: X can be -S02-, -SO-, - (CH2) P-, - (CH2) p-0-, - (CH2) P- (C = 0) -, - (CH2) p- (C = 0) -NH-, - (CH2) p-CH0H-, -CHOH- (CH2) p-, - (CH2) P-CH = CH-, -CH = CH- (CH2) P- with p = 1 ... 4, Y can be - (C = 0) -, - (C = 0) -NH-, - (C = 0) - NH- (CH2) P-, - (C = 0) - (CH2) p-, - (CH2) P-, - (CH2) p-0-, - (CH2) P- (C = 0) -, - (CH2) p- (C = 0) -NH-, - (CH2) p- (C = 0) -NH- (CH2) p-, - (CH2) p -CH0H-, -CH0H- (CH2) p-, - (CH2) P-CH = CH-, -CH = CH- (CH2) p- with p = 1 ... 4, Z can be -O-, -0- (CH2) p- with p = 1 ... 4, -NH-, -NH- (C = 0) -, -NH- (C = 0) -NH-, -NH- (C = 0) -0-, -NH-CH2- (C = 0) - and -NH- (C = 0) -CH2-, R, R and R can be the same or different and have the following meaning: mono, bi or tricyclic carbocycles saturated or mono or polyunsaturated with 5 .. .14 ring members, in particular phenyl, naphthyl, anthranil, fluorenyl; or mono, bi or tricyclic saturated or mono- or polyunsaturated heterocycles with 5-15 ring members and 1 ... 6 heteroatoms, which preferably are N, 0 and S, in particular thiophenyl, pyridinyl, isoxazolyl, benzimidazolyl, benzyl (1) , 3) dioxolyl, pyrimidinyl, quinolyl, quinazolinyl, morphononylyl, pyrrolidinyl, pyrrolyl, phenyl (1, 2, 4) oxadiazolyl, phenylthiazolyl, wherein carbocycles or heterocycles may be mono- or polysubstituted with: C? ... 6 ~ alkyl, -0-C? ... 6_ alkyl, -0-C3-cycloalkyl, mono, bi or tricyclic saturated or mono- or poly-unsaturated carbocycles with 3 ... 14 ring members, saturated mono, bi or tricyclic heterocycles or mono or polyunsaturated with 5-15 ring members and 1 ... 6 heteroatoms, which preferably are N, 0 and S, -F, -Cl, -Br, -I, -OH, -SH, -N02, -NH2, -NHC? ... 6- alkyl, -N (C? ... 6-alkyl) 2, -NHC6 ...? -aryl, -N (C6 ...? 4- aryl) 2, -N ( C1 ... 6-alkyl) (C6 ...? 4-aryl), -NHC0C? ... 6- alkyl, -NHCOC6 ...? 4-aryl, -C0NH C? ... 6-alkyl, CONHC6 ... 14-aryl, -CONHS02C? ... 6-alkyl, -CONHS02C6 ...? 4- aryl, -CN, - (CO) C? ... 6 -alkyl, - (CS) Cj .... 6-alkyl, -COOH, -COOC? ... 6-alkyl, -0-C6 ...? 4-aryl, -O- (CO) C ?. ..6- alkyl, -O- (CO) C6 ...? -aryl, benzyl, benzyloxy, -S-C? ... 6-alkyl, -S-C6 ... i4-aryl, -CF3, - (CH2) p-COOH with p = 1 to 4, - (CH2) p-COOC? ... 6-alkyl with p = 1 to 4, -S02- C? ... 6-alkyl, -S02- C6 ...? - aryl, R1 can also be H (however not when X = CH2) R -Z can also be N02, however with the exception of the compounds according to formula I: when Z is equal to -NH- (C = 0) -, -NH- (C = 0) -NH-, - NH- (C = 0) -CH2- and simultaneously R1 = mono or poly phenyl substituted with -COOH, -COOC? ... 6-alkyl, - (CH2) p-COOH with p = 1 to 4, - (CH2 ) p-C00C? ... 6-alkyl with p = 1 ... 4, -CONHC? ... 6-alkyl, -CONHC6 ...? 4-aryl, -CONHS02C1 ... 6-alkyl, - CONHS02C6 ...? - aryl, lH-tetrazol-5-yl, then R2 can not be equal to phenyl mono or polysubstituted with CN, halogen, C? ... 4-alkyl, C? ... 4-alkyloxy, CF3, furthermore, when R3-Z = N02, then Rx-X and R2-Y can not simultaneously have the following meaning: R1-X = benzyl, 4-methoxybenzyl R2-Y = benzyl, 2-picolyl.

2. Compounds according to claim 1, 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-methoxy-benzolsulfonyl) -1,2-dihydroindazol-3-one 2- (2-hydroxy) 5-Nitrobenzyl) -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-nitrobenzyl) -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one -tri-fluormetoxy-benzolsulfonyl) -1,2-dihydro-indazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-chlorobenzolesulfonyl) -1,2-dihydro -indazol-3-one 1- (4-fluorobenzenesulfonyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1,2-dihydro-indazol-3-one N- (4- [2- ( 2-hydroxy-5-nitrobenzyl) -5-methoxy-3-oxo-2,3-dihydro-indazol-l-sulfonyl] -phenyl) -acetamide 2- (4-fluorobenzyl) -5-methoxy-l- (toluol -4-sulfonyl) -1,2-dihydro-indazol-3-one 2- (4-fluorobenzyl) -5-methoxy-1- (4-chlorobenzolsulfonyl) -1,2-dihydro-indazol-3-one 1- (4-Fluorobenzolsulfonyl) -2- (4-fluorobenzyl) -5-methoxy-1,2-dihydro-indazol-3-one 2- (2-fluorobenzyl) -5-methoxy-1- (toluol-4-sulfonyl) -1, 2-dihydro-indazol-3-one 1- (4-fluorobenzenesulfonyl) -2- (2-fluorobenzyl) -5-methoxy-1,2-dihydro-indazol-3-one 2- (3-methoxybenzyl) -5 -methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 2- (3-trifluoromethyl-benzyl) -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro- indazol-3-one 2- [2- (4-chlorophenyl) thiazol-4-ylmethyl] -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 5-methoxy -2- (3-phenylalyl) -1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 5-methoxy-2- (3-oxo-3-phenylpropyl) -1- (toluol -4-sulfonyl) -1,2-dihydro-indazol-3-one 2- [2- (2,6-difluorphenoxy) ethyl] -5-methoxy-1- (toluol-4-sulfonyl) -1, 2- dihydro-indazol-3-one 2- [2- (2-bromo-4,6-difluorphenoxy) ethyl] -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazole-3- 2- [2- (2-Bromo-4,6-difluorphenoxy) ethyl] -5-methoxy-1- (4-methoxy-benzolsulfonyl) -1,2-dihydro-indazol-3-na N- (4-na) - { 2- [2- (2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-yl) ethyl] -5-methoxy-3-oxo-2,3-dihydro-indazole-1 -sulfonyl.}. -phenyl) -acetamide 2-. { 3- [4- (3-chlorophenyl) -piperazin-1-yl] propyl} -5-methoxy-1- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 1- (4-chlorobenzolsulfonyl) -2-. { 3- [4- (3-chlorophenyl) -piperazin-1-yl] propyl} -5-methoxy-l- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one N-benzyl-2- [5-methoxy-3-oxo-l- (toluol-4-sulfonyl) -1, 3-dihydro-indazol-2-yl] -acetamide 2- [5-methoxy-3-oxo-l- (toluol-4-sulfonyl) -1, 3-dihydro-indazol-2-yl] -N - (4-methoxyphenyl) -acetamide 2- (2,6-dichlorobenzoyl) -5-nitro-l- (toluol-4-sulfonyl) -1,2-dihydro-indazol-3-one 1- (3, 4- dichlorobenzyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methylthio-1,2-dihydro-indazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (3 -nitro-benzyl) -1, 2-dihydro-indazol-3-one (2-fluorophenyl) -amide of 5-methoxy-1- (3-nitrobenzyl) -3-oxo-l, 3-dihydro-indazole- 2-methoxy-l- (3-nitrobenzyl) -3-oxo-l, 3-dihydro-indazole-2-carboxylic acid 2-carboxylic acid (2-6-dichloro-phenyl) -amide (2-fluoro-6-trifluoromethylphenyl) 5-methoxy-1- (3-nitro-benzyl) -3-oxo-l, 3-dihydro-indazole-2-carboxylic acid amide 3- [2- (2-fluorophenylcarbamoyl) -5- methyl ester methoxy-3-oxo-2,3-dihydro-indazol-l-ylmethyl] -benzoic acid (2,6-dichloro-phenyl) -am l- (4-Fluoro-benzyl) -5-methoxy-3-oxo-l, 3-dihydro-indazole-2-carboxylic acid 1- (4-fluorobenzyl) -5-methoxy-4-nitrobenzyl ester 3-Oxo-l, 3-dihydro-indazole-2-carboxylic acid (2,6-dichloro-phenyl) -amide of 1- (2,6-difluor-benzyl) -5-methoxy-3-oxo-l, 3- di (2-chloro-6-fluorobenzyl) -5-methoxy-3-oxo-l, 3-dihydro-indazole-2-carboxylic acid dihydro-indazole-2-carboxylic acid (2,6-dichloro-phenyl) -amide

3. Physiologically tolerable salts of the new compounds according to formula I according to claims 1 and 2, characterized by the neutralization of the bases with inorganic or organic acids, or by the neutralization of the acids with inorganic or organic bases or by the Quaternization of tertiary amines to quaternary ammonium salts.

4. Use of the compounds according to formula I and their salts according to claims 1 to 3 as therapeutic active ingredients for the preparation of medicaments for the treatment of diseases mediated by PPlase.

5. Particularly preferred use of the compounds according to formula I and their salts according to claims 1 to 3 as therapeutic active ingredients for the preparation of medicaments for the treatment of diseases related to the inhibition of immunological processes.

6. Processes for the preparation of the compounds of the general formula I according to claims 1 to 3, characterized in that a) for X = -S02-, -SO- is proceeded according to the scheme 1, so that lH-indazol-3-ylsulphonic acid II formula II esters are reacted in the presence of a base, and eventually in the presence of a diluent, to obtain compounds of the general formula III formula III wherein R1, R3, X and Z have the meaning mentioned in claim 1 or in the foregoing, and that esters of lH-indazol-3-ylsulfonic acid II or 1-sulfonyl-indazoles III are reacted, optionally in presence of a base, in particular sodium hydride, and optionally in the presence of a diluent, in particular dimethylsulfoxide, with compounds of the following general formulas: Hal-Y-R2, 0 = C = N- (CH2) p-R2, ( R2- (CH2) PC = 0) 20 with p-wherein R1, R2, R3, X, Y and Z have the meaning mentioned in claim 1 or above, and Hal means a halogen atom F, Cl, Br or iodo, to obtain compounds of the general formula I, wherein R1, R2, R3, X, Y and Z have the meaning mentioned in claim 1 or in the foregoing, b) for X = - (CH2) P- , - (CH2) p-0-, - (CH2) P- (C = 0) -, - (CH2) p- (C = 0) -NH-, - (CH2) p-CH0H-, -CHOH- (CH2) p-, - (CH2) p-CH = CH-, -CH = CH- (CH2) P- with p = 1 ... 4, proceed according to scheme 2, so that they are reacted compounds of the general formula III, optionally in the presence of a base, in particular pyridine or sodium hydride, and optionally in the presence of a diluent, in particular tetrahydrofuran or dimethyl sulfoxide, with compounds of the following general formulas: Hal-Y-R2, 0 = C = N- (CH2) p-R2, (R2- (CH2) pC = 0) 20 with p = 0 ... 5 where R1, R2, R3, X, Y and Z have the meaning mentioned in claim 1 or in the foregoing, and Hal means a halogen atom F, Cl, Br or iodine, to obtain compounds of the general formula I, wherein R1, R2, R3, X, Y and Z have the meaning mentioned in claim 1 or in the foregoing, wherein formula III may also exist as a tautomeric form of formula IV formula IV according to scheme 3.

7. Pharmaceutical remedy characterized in that as an active component it contains at least one compound of the formula I according to claims 1 to 3 and vehicles and / or diluents or physiologically tolerable adjuvants.

8. Pharmaceutical preparations characterized in that they contain at least one compound of the formula I according to claims 1 to 3 and a suitable vehicle as an active component.

9. Pharmaceutical preparations according to claims 1, 2, 3, 7 and 8, characterized in that they are administered in the form of tablets, dragees, capsules, aerosols, powder formulations, plasters, solutions, ampoules or suppositories.

10. Use of the compound of the formula I according to claims 1 to 3 and / or of the pharmaceutical preparations according to claims 7 and 8 as a remedy with anti-asthmatic, antiallergic, inflammation inhibitory and / or immunomodulating activity, either alone or in combination of some with others or in combination with vehicles.